Arteriosclerosis is one of the diseases suffered by an increasing population of adults and even adolescents and children, often caused by dietary changes.
While a number of risk factors, either genetic or environmental, for the attack and progress of arteriosclerosis have been reported, recent studies have singled out elevated plasma cholesterol levels as a primary risk factor. Therefore, a great deal of attention has been devoted to the establishment of relationships between the level of blood lipoproteins or lipids and the risk of developing a coronary heart disease. As is well known, both high density lipoproteins(HDL) and low density lipoproteins(LDL) carry cholesterol in human blood mainly in the form of cholesteryl esters(CE). Specifically, HDL serves to transport cholesterol that remains in peripheral cells back to the liver, where cholesterol is decomposed and eliminated. Since, therefore, cholesterol can be easily eliminated when it is carried by HDL, plasma cholesterol levels can be effectively decreased by blocking the transfer of cholesterol from HDL to other lipoproteins.
In this connection, CETP transfers CE from HDL to LDL or very low density lipoproteins(VLDL); and there have been extensive studies on its function. For instance, Drayna et al. have determined the cDNA sequence of human CETP and successfully cloned it(Nature, 327, 6123(1987)); and Wang et al. have reported the production of human CETP using a vector comprising cDNA of human CETP(DNA, 8, 753-758(1989)).
Kushwaha et al. have reported that several species of animals which lack CETP have high HDL-cholesterol levels and low LDL-cholesterol levels, and, further, show a low rate of arteriosclerosis attack(J. of Lipid Research, 34, 1285-1297(1993)). This fact suggests an important interrelationship among CETP, cholesterol levels and attack of arteriosclerosis.
Further, familial members lacking CETP in Japan have been reported to have large HDL particles and to live long without occurrences of heart diseases(Koizumi et al., Arteriosclerosis, 58, 175-186(1986)). Recently, Marotti et al. have reported that when mice lacking CETP were transformed with a heterogenous CETP gene, serious arteriosclerosis occurred in transgenic mice in comparison with a reference mouse group(Nature, 364, 73--73(1986)).
These observations tend to support the hypothesis that, if CETP is made deficient or its activity is inhibited, transfer or elimination of cholesterol through HDL will be promoted, thereby rendering it possible to prevent or treat diseases caused by high levels of cholesterol, e.g., arteriosclerosis.
FIG. 1 shows a schematic view of the role of CETP and interrelationship between CETP and its inhibitor in the cholesterol reverse-transportation pathway. As shown in FIG. 1, cholesterol is carried by HDL in the form of CE, and transferred to LDL by CETP. CE in LDL is transferred to peripheral areas and accumulates in the cells, while CE in HDL is transported to the liver, where it is decomposed and eliminated.
When the amount of CE to be transported exceeds the transporting capacity of HDL, then CE becomes deposited in the cells in certain critical areas such as arterial walls. Such accumulation eventually results in impaired cell functions and, if continued, may cause cell death, which may, in turn, lead to the accumulation of cellular debris in the wall of blood vessels to induce atherosclerosis. In this case, however, if the action of CETP is inhibited or blocked, CE in HDL will not be transferred to LDL and will be transported to liver, thereby preventing or minimizing the accumulation of CE at, e.g., the wall of blood vessels, and the occurrence of arteriosclerosis.
In this context, many attempts have been made to inhibit or lower the CETP activity in order to lower the plasma cholesterol levels.
U.S. Pat. No. 5,279,540 discloses a method for lowering blood CETP concentration in an arteriosclerosis patient by passing the patient's blood through an anti-CETP column to treat arteriosclerosis.
PCT Publication No. WO 93/11782 discloses a peptide which is separated from the blood plasma of baboon and has a CETP inhibiting activity; amino acid sequence thereof; and a synthetic peptide prepared on the basis of said sequence which has a CETP inhibiting activity equal to that of natural one.
However, there still exists a need for a CETP inhibitor peptide having an excellent CETP inhibiting activity.